Clinical implications from the European Heart Rhythm Association consensus document on antiarrhythmic drug therapy

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Address for correspondence: Dr. Bülent Görenek, Eskişehir Osmangazi Üniversitesi, Tıp Fakültesi, Kardiyoloji Anabilim Dalı, Meşelik Kampüsü, Eskişehir-Türkiye

Phone: +90 222 229 22 66 E-mail: bulent@gorenek.com Accepted Date: 13.04.2018

Invited Review

Emin Evren Özcan, Bülent Görenek

1

Department of Cardiology, Faculty of Medicine, Dokuz Eylül University; İzmir-Turkey

1_{Department of Cardiology, Faculty of Medicine, Eskişehir Osmangazi University; Eskişehir-Turkey}

Clinical implications from the European Heart Rhythm Association

consensus document on antiarrhythmic drug therapy

Introduction

Despite revolutionary developments concerning catheter ablation therapies and device technologies, little has changed in pharmacological antiarrhythmic therapy over the last de-cades. Currently, antiarrhythmic drugs (AADs) are far away to cure arrhythmias, but they are an important treatment option for suppressing them, and they are widely used. Although many guidelines have been published to determine AAD indications, pharmacological treatment strategies are highly variable in clini-cal practice, and evidence-based medicine is less applied com-pared with other treatment modalities.

For this purpose, the European Heart Rhythm Association (EHRA) and the European Society of Cardiology Working Group on Cardiovascular Pharmacology convened a Task Force, with representation from the Heart Rhythm Society and Asia Pacific Heart Rhythm Society, published a practical document classify-ing antiarrhythmic treatment options and summarizclassify-ing the in-dications and side effects (1). This consensus document offers valuable recommendations in detail. Here, we will focus on novel concepts in pharmacological antiarrhythmic therapy and less known but important recommendations, not covering all details.

Paradigm shift in treatment strategy and drug development Initially, the authors classified AADs and reviewed the recent developments in clinical pharmacology. The widely used

tradi-tional Singh–Vaughan Williams classification based on the ef-fects of AADs on cardiac ion channels is explained in detail (2). Next, limitations of this empirical approach are compressively discussed, and a new pathophysiological approach is offered. The traditional approach is based on the AAD properties with the final aim of altering the excitability, conduction, or automaticity, irrespective of the specific mechanism of arrhythmia; however, the modern AAD therapy is based on discovering the critical components of arrhythmia and identifying the vulnerable param-eters. For example, the mechanism of an atrioventricular (AV) nodal re-entrant tachycardia is a re-entry in the AV node, and because it generates L-type calcium channel-dependent action potentials, the arrhythmia can be targeted by calcium channel blockers, adenosine, or beta-blockers. Unfortunately, in many pa-tients, the underlying mechanisms of arrhythmias are not clear; thus, the authors agree the need of an empiric AAD therapy based on the diagnosis.

This novel approach requires a better understanding of the action potential rather than the empirical antiarrhythmic therapy. Understanding the details of membrane action potential is cru-cial for both effective treatment and less side effects. The au-thors summarize the paradigm shift in AAD development and provide some examples of novel drugs

Vernekalant blocks INa channels at faster rates and at more positive action potential. The atrial membrane potential is more

The recently published consensus document by the European Heart Rhythm Association presents a patient-tailored pharmacological antiarrhyth-mic treatment approach targeting the arrhythmia mechanism. This document comprehensively reviews the indications, side effects, and contrain-dications of antiarrhythmic drugs. In this paper, we reviewed novel treatment concepts offered by the consensus document.

(Anatol J Cardiol 2018; 20: 48-51)

Keywords: antiarrhythmic drugs, pharmacological antiarrhythmic therapy, proarrhythmia, pharmacokinetics, pharmacodynamics

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BSTRACT

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positive than the ventricular membrane potential, and this dif-ference increases during tachycardia. Therefore, it is called an atrial-specific drug. These properties of vernekalant imply a low-er risk of ventricular proarrhythmia, particularly when the heart rate slows in heart failure patients.

Ranolazine, a drug with antianginal properties, has a high affinity for late component of the sodium current (INa_L). The Ranolazine Implantable Cardioverter-Defibrillator study demon-strated a significant reduction in ventricular tachycardia with ranolazine (3).

Other potential future AADs that will target different param-eters such as excitability and effective refractory period (IKur and TASK channels), re-entry and refractoriness (I_SK), and atrial remodeling through Ca2+_{signaling molecules (calpains,}

calci-neurin) are also reviewed (4).

New concept: The patient, the arrhythmia, and the drug Patient-tailored drug selection is a novel concept offered by the consensus document. Authors underline the difference be-tween treating the disease and treating the arrhythmia. They re-mind the The Cardiac Arrhythmia Suppression Trial (CAST) study as an example, how effective antiarrhythmic therapy can be potentially dangerous, particularly in the presence of structural heart disease (5). The decision to start therapy should balance the efficacy and safety.

The patient

The consensus document individualizes the recommenda-tions for pharmacological therapy based on patient’s character-istics. The presence of an arrhythmia in a patient with structural heart disease is not an unusual condition. Unfortunately, these patients have higher risks of proarrhythmia with AADs. The au-thors state valuable recommendations related with four different clinical entities:

• Class IA, IC, and III membrane-active AADs other than amio-darone or sotalol, are not recommended in patients with sig-nificant structural heart disease, such as cardiomyopathy, left ventricular dysfunction, myocardial infarction, and myo-cardial ischemia. The authors emphasize that sotalol is asso-ciated with increased mortality due to proarrhythmia and can be used in patients with coronary artery disease preferably with an implantable cardiodefibrillator (ICD) (6).

• It is advised to avoid the use of Class IA, IC, and III AADs in patients with substantial LVH (≥1.4 cm) other than amioda-rone, dronedaamioda-rone, or sotalol and disopyramide.

• Disopyramide is recommended in patients with obstructive hypertrophic cardiomyopathy for symptom improvement. In patients with atrial fibrillation, it can increase the ventricular rate and should be used with beta-blockers.

• In the presence of congenital heart disease, AADs should be reserved to selected cases because they are frequently poorly tolerated due to negative inotropic effects.

Patients with tachyarrhythmia and pre-existent bradycardia

or conduction disturbances present another challenging sce-nario. All AADs may induce bradycardia or may cause AV con-duction block. Caution is warranted in all patients with a history of syncope, sinus bradycardia, or AV conduction disturbances including PR prolongation.

Although the consensus report recommends implantation of a pacemaker before the initiation of AAD in patients with symp-tomatic bradyarrhythmias, it is reasonable to offer ablation as an alternative to pacemaker implantation. We believe that many tachyarrhythmias can be cured with ablation and that the need for pacemaker implantation can be canceled or at least post-poned. It should be kept in mind that sodium channel blockers (Class IA and IC) may increase the pacing threshold, but this is rarely clinically relevant.

Although the efficacy of AAD therapy appears to be similar in men and women, the risk of proarrhythmias appears to be great-er in women than in men (7). Physiological changes in oldgreat-er age significantly affect the pharmacokinetics of AADs and increase the risk of proarrhythmia (8). Similarly, reduction in renal func-tion may have important implicafunc-tions for antiarrhythmic therapy. Procainamide and sotalol should be avoided in patients treated with hemodialysis. The dose of flecainide should be at least half of the usual recommended dose. Conversely, dialysis has little impact on amiodarone clearance, and no dosage adjustment is necessary (9).

The arrhythmia

The management of arrhythmias and therapies related with them are comprehensively discussed in the document. Each type of arrhythmia individually reviewed, drugs of choice, their rec-ommended doses, contraindications, and precautions are listed in the related tables. Flow charts prepared for specific clinical conditions facilitate to remember the management of different scenarios.

The drug

It should be kept in mind that most of AADs have a narrow therapeutic window and that almost all AADs may produce pro-arrhythmic effects. Unfortunately, both underlying diseases and comorbidities are dynamic. Therefore, not only a careful pre-ad-ministration assessment but also a follow-up for proarrhythmic effects is indicated (10). Appropriate laboratory and diagnostic tests should be part of the follow-up protocol; these tests should include ECG and other tests according to the patient’s profile and AAD characteristics.

The pharmacokinetics and pharmacodynamics of AADs are discussed in detail. The absorption, distribution, biotransforma-tion, and elimination of drugs are summarized with particular ex-amples. For example, propafenone increases the plasma levels of digoxin, metoprolol, propranolol, and warfarin. Dose adjust-ment recommendations are included for commonly used drug combinations in daily practice. For example, non-antivitamin K oral anticoagulant dose reduction should be considered when

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amiodarone is a concomitant medication. Dabigatran and edoxa-ban dose reduction is also recommended when taken simultane-ously with verapamil. All AADs have interactions, and drug in-teractions are described on two pages. The authors recommend evaluating the possible interactions of any antiarrhythmic drug with any concomitant therapy using web-based tools (e.g., www. drugs.com, www.crediblemeds.org). The importance of monitor-ing AADs and indications for pharmacokinetic monitormonitor-ing is also listed.

Is it safe to initiate AAD out of the hospital?

Initiation of any AAD implies some risk of adverse event, in-cluding proarrhythmic effects. For this reason, when the risk of proarrhythmia is high, in-hospital drug initiation is recommended (11). However, for financial and practical reasons, this approach is limited to selected patients at high risk.

The high-risk criteria for Class IC AADs are bundle branch block or a wide QRS duration (>120 ms), structural heart disease, left ventricular dysfunction (<0.40), tachyarrhythmia with a rapid ventricular response, history of ventricular tachyarrhythmias, or concurrent treatment with drugs having a negative inotropic ef-fect.

The high-risk criteria for Class IA and class III AADs are a QT interval (QTc >460 ms), female sex, bradycardia or long-RR intervals, excessive QT/QTc lengthening during treatment (>550 ms or >25% over baseline), structural heart disease, left ventricular hypertrophy, heart failure, hypokalemia or hypomag-nesemia, or reduced renal function. In-hospital drug initiation is rarely indicated for amiodarone because of its slow onset action and long half-life.

Previous in-hospital testing with intravenous flecainide or propafenone did not predict the safety of the “pill-in-the-pocket” approach and is not recommended by the document (12).

Safety issues for patients treated with antiarrhythmic drugs Initially, mechanisms promoting proarrhythmia are reviewed. Drug–substrate and drug–drug interactions associated with pro-arrhythmia are listed. The authors not only discuss the factors facilitating proarrhythmia but also offer life-saving treatment op-tions. For example, they offer three key actions for drug-induced torsade de pointes (TdP):

• Intravenous administration of magnesium sulfate, irrespec-tive of serum magnesium levels (i.e., 2 g bolus followed by another 2 g bolus and by continuous infusion in case of ar-rhythmia persistence).

• Increasing heart rate (to reverse bradycardia and to prevent pauses that may prolong repolarization and promote TdP) by means of isoproterenol or overdrive pacing at rates >70 beats per minute.

• Correction of hypokalemia, replenishing serum potassium to the high-normal range (i.e., 4.5-5.0 mEq/L).

As we discussed above, AADs cannot cure but suppress ar-rhythmias. That means long term, sometimes life-long treatment.

Therefore, extracardiac toxicities are not rare. Drug-specific side effects are listed in a table. Particularly, the toxicity of amio-darone is comprehensively reviewed. The importance of follow-up and patient education is emphasized.

Conclusion

The consensus document presents a patient-tailored antiar-rhythmic treatment approach that targets the arrhythmia mecha-nism. It provides a perspective on future drugs and summarizes the indications of currently available drugs, along with their side effects and contraindications. This document is so intense that it would not be an exaggeration to call this document as a sum-mary of the previous EHRA guidelines.

Conflict of interest: None declared. Peer-review: Internally peer-reviewed.

Authorship contributions: Concept – E.E.Ö., B.G.; Design – B.G.; Su-pervision – B.G.; Literature search – E.E.Ö.; Writing – E.E.Ö., B.G.; Critical review – B.G.

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